Each year ~1.5 million American women between ages of 45 and 55 enter into the perimenopause. Yet to be discovered is the impact perimenopause has on key brain regions involved in cognition and known to be vulnerable to Alzheimer's disease (AD). Women have a higher lifetime risk of developing AD and represent more than 60% of the Alzheimer's disease population. The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project is to discover the biological transformations that occur in the brain during the perimenopausal transition that can result in phenotypes at risk for development of Alzheimer's pathology. We seek to identify the mechanisms by which these changes occur and to translate these discoveries to determine the optimal timing and strategies for preventing conversion to the perimenopausal at-AD-risk phenotype. To achieve our mission, we have developed a focused research center model with an integrated set of four Projects and three Cores. Projects 1, 2 and 3 are basic, mechanistic and preclinical translational science investigations of the perimenopausal brain utilizing our program developed rodent models of human perimenopause. Project 4 uses the results of Project 1, 2 and 3 to inform its ancillary association analysis of existing data and samples from the NIA-funded clinical trial Early versus Late Intervention Trial with Estrogen (ELITE) (R01AG-024154). To achieve our Program mission, each project has a unique but complementary research focus with all Aims of all projects and cores addressing Program wide aims. Innovative and integrative features of our Program include: bidirectional translational research; rodent models of human perimenopause transition; custom designed gene arrays that include GWAS identified AD risk factor genes and bioenergetic, inflammatory and AD system pathways, shared customized data and document management. Program-wide gene array and bioinformatic analyses across all projects. Discovery of at-AD-risk phenotypes and the underlying mechanisms of phenotype development could potentially lead to the early identification of those at greatest risk for developing AD and mechanistically inform interventions to prevent the disease. Program research addresses NIA Strategic Goals A and C.